Soluble estradiol capsule for vaginal insertion

ABSTRACT

According to various embodiments of this disclosure, pharmaceutical formulations comprising solubilized estradiol are provided. In various embodiments, such formulations are encapsulated in soft capsules which may be vaginally inserted for the treatment of vulvovaginal atrophy.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a nonprovisional application of and claims priorityto the following: U.S. Provisional Patent Application No. 61/745,313,entitled “SOLUBLE ESTRADIOL CAPSULE FOR VAGINAL INSERTION,” which wasfiled on Dec. 21, 2012. All aforementioned applications are herebyincorporated by reference herein in their entirety.

BACKGROUND Field

Postmenopausal women frequently suffer from certain vaginally localizedstates including, for example, atrophic vaginitis or vulvar and vaginalatrophy (hereinafter “vulvovaginal atrophy” or “VVA”) with symptomsincluding, for example, dryness, itching, soreness, irritation, bleedingand dyspareunia; with urinary frequency, urgency, urinary discomfort andincontinence also occurring (singularly and collectively,“estrogen-deficient urinary state(s)”). For the sake of clarity, theterms “atrophic vaginitis” and vulvovaginal atrophy are used hereininterchangeably. The molecular morphology of VVA is well known in themedical field.

Each of these WA-related states, inter alia, are symptoms associatedwith decreased estrogenization of the vulvovaginal tissue, and can evenoccur in women treated with oral administration of an estrogen-basedpharmaceutical drug product. Although WA is most common with menopausalwomen, it can occur at any time in a woman's life cycle.

WA-related states are generally treated with local administration of anestrogen-based natural or synthetic hormone in the form of a topicallyapplied gel or cream, or through vaginal insertion of a compressedtablet. These forms of administration can provide low levels ofcirculating estrogen but are not intended to contribute to the treatmentof other states related to estrogen deficiencies typically treated viaadministration of a systemically absorbed estrogen product. For example,such systemically absorbed products include orally administeredformulations as well as creams, gels, sprays, and transdermallydelivered products. However, vaginal gels and creams may rub, wear orwash off before the estrogen is fully absorbed into the local tissue. Inaddition, various commercially available estrogen-containing creamscontain an alcohol such as benzyl alcohol and/or stearyl alcohol. Theuse of such products may result in itching or burning when applied. Theabove referenced vaginal creams and gels require insertion via areusable vaginal applicator/plunger for which patients complain ofdifficulty to accurately dose, discomfort or pain upon insertion, andincreased trauma to the genital mucosa all in relation to the vaginalapplicator. Furthermore, the reusable applicator/plunger is alsodifficult to clean resulting in hygienic concerns as well as increasedrates of infection all decreasing the ongoing compliance of the therapy.

Similarly, vaginal suppositories in the form of inserted tablets may notfully dissolve, reducing the effective dose of absorbed estrogen; maycause unwanted and unnecessary vaginal discharge; may cause an increaseof vulvovaginal pruritus and/or back pain; and the insertion, itself,using the applicator provided with the reference-listed tableted drug,Vagifem® (Novo Nordisk; Princeton, N.J.), may cause a rupture of thevaginal fornix.

There has been at least one attempt at providing a soluble or suspendedestrogen capsule for vaginal insertion as described in U.S. Pat. No.6,060,077 (the '077 patent). The '077 patent provides for a non-systemictreatment for vaginal dryness in menopausal women using an immediate orslow-release formulation comprising a natural estrogen compound insolution or suspension in a lipophilic agent, a hydrophilic gel-formingbioadhesive agent, a gelling agent for the lipophilic agent, and ahydrodispersible agent in a hard or soft capsule. It is specificallystated that these formulations are designed to avoid systemic passage ofestradiol following administration. Once in contact with vaginalsecretions, these formulations require the presence of the hydrophilicgel-forming bioadhesive agent to react with the hydrodispersible agentto form an estrogen-containing emulsion to facilitate absorption. Apractical issue arises when attempting to use this medicament whenvaginal secretions are required to activate the formulation while thetreatment is designed to treat vaginal dryness.

Accordingly, an estrogen-based vaginal suppository that provides an easeof administration/insertion, improved safety of insertion, lacking orminimizing vaginal discharge following administration, and that does notrequire vaginal secretions to activate the formulation could provide amore effective dosage form with improved efficacy, safety and patientcompliance.

SUMMARY

According to various embodiments of this disclosure, encapsulatedpharmaceutical formulations comprising solubilized estradiol areprovided. Such formulations are encapsulated in soft capsules which arevaginally inserted for the treatment of vulvovaginal atrophy.

BRIEF DESCRIPTION OF THE DRAWINGS

The subject matter of the present invention is particularly pointed outand distinctly claimed in the concluding portion of the specification. Amore complete understanding of the present invention, however, may bestbe obtained by referring to the detailed description and claims whenconsidered in connection with the drawing figures, wherein like numeralsdenote like elements and wherein:

FIG. 1 is a flow diagram illustrating a process in accordance withvarious embodiments; and

FIG. 2 illustrates a suppository in accordance with various embodiments.

DETAILED DESCRIPTION OF THE ILLUSTRATED EMBODIMENTS Definitions

The term “active pharmaceutical ingredient” as used herein, means theactive compound(s) used in formulating a drug product.

The term “AUC,” as used herein, refers to the area under the curve thatrepresents changes in blood concentration of estradiol or estrone overtime.

The term “bioavailability”, as used herein means the concentration of anactive ingredient (e.g., estradiol or estrone) in the blood (serum orplasma). The relative bioavailability may be measured as theconcentration in the blood (serum or plasma) versus time. Otherpharmacokinetic (pK) indicators may be used to measure and assessbioavailability, determined by suitable metrics including AUC, C_(max,)and, optionally, T_(max).

The term “bioequivalent” means that a test drug product provides similarbioavailability compared to a reference listed drug product pursuant tothe criteria set forth for bioequivalence by the United States Food andDrug Administration, as amended.

The term “bio-identical hormones”, as used herein, means thosesynthetically-derived compounds which are identical in chemicalstructure to the hormones naturally produced in vivo. These natural orbio-identical hormones are synthesized from various ingredients to matchthe chemical structure and effect of estradiol or estrone, or estriol(the 3 primary estrogens).

The term, “C_(max)” as used herein, refers to the maximum value of bloodconcentration shown on the curve that represents changes in bloodconcentrations of estradiol and/or estrone over time.

The term “co-administered” as used herein, means that two drug productsare administered simultaneously or sequentially on the same or differentdays.

The term “drug product” as used herein means at least one activepharmaceutical ingredient in combination with at least one excipient andprovided in unit dosage form.

The term “excipients,” as used herein, refer to non-activepharmaceutical ingredients such as carriers, solubilizing agents, oils,lubricants and others used in formulating pharmaceutical products. Theyare generally safe for administering to animals, including humans,according to established governmental standards, including thosepromulgated by the United States Food and Drug Administration.

The term “natural,” as used herein with reference to hormones discussedherein, means bio-identical hormones synthesized to match the chemicalstructure and effect of those that occur naturally in the human body(endogenous). An exemplary natural estrogen is estradiol (also describedas 17β-estradiol and E2).

The term “medium chain,” as used herein means any medium chaincarbon-containing substance, including C4-C18, and including C6-C12substances, fatty acid esters of glycerol, fatty acids, and mono-, di-,and tri-glycerides of such substances.

The term “reference listed drug” as used herein means Vagifem®.

The term “solubilizer,” as used herein, means any substance or mixtureof substances that may be used to enhance the solubility of estradiol,including, for example and without limitation, appropriatepharmaceutically acceptable excipients, such as solvents, co-solvents,surfactants, emulsifiers, oils and carriers.

The term “treatment”, as used herein, or a derivative thereof,contemplates partial or complete inhibition of the stated disease stateor condition when a formulation as described herein is administeredprophylactically or following the onset of the disease state for whichsuch formulation is administered. For the purposes of the presentdisclosure, “prophylaxis” refers to administration of the activeingredient(s) to an animal, typically a human, to protect the animalfrom any of the disorders set forth herein, as well as others.

The term, “Tmax” as used herein, refers to the time that it takes forestradiol and/or estrone blood concentrations to reach the maximumvalue.

Description

Provided herein are pharmaceutical formulations comprising solubilizedestradiol; providing said formulations do not embrace within the fillone or more of the following components: a hydrophilic gel-formingbioadhesive agent; a lipophilic agent; a gelling agent for thelipophilic agent, and/or a hydrodispersible agent. The hydrophilicgel-forming bioadhesive agent may provide or exclude one or more of a:carboxyvinylic acid; hydroxypropylcellulose; carboxymethylcellulose;gelatin; xanthane gum; guar gum; aluminum silicate; or mixtures thereof.The lipophilic agent may provide or exclude one or more of a: liquidtriglyceride; solid triglyceride (with a melting point of about 35° C.);carnauba wax; cocoa butter; or mixtures thereof. The gelling agent mayprovide or exclude one or more of a hydrophobic colloidal silica. Thehydrodispersible agent may provide or exclude one or more of a:polyoxyethylene glycol; polyoxyethylene glycol 7-glyceryl-cocoate andmixtures thereof.

Generally, the pharmaceutical formulations described herein are preparedand administered as filled capsules, typically soft capsules of one ormore materials well known in the art including, for example and withoutlimitation, soft gelatin capsules. However, in various embodiments,pharmaceutical formulations described herein are prepared as a gel,cream, ointment, transdermal delivery system or like preparation.

Other aspects of the present disclosure include the use of formulationsas described herein for the treatment of vulvovaginal atrophy includingthe treatment of at least one VVA symptom including, for example andwithout limitation, dryness, itching, soreness, irritation, bleeding anddyspareunia.

Another aspect of the present disclosure provides uses of theformulations described herein for the treatment of estrogen-deficienturinary states.

Another aspect of the present disclosure provides alcohol-free orsubstantially alcohol-free formulations, and uses thereof. Among others,the formulations offer improved comfort during use, thus tending toenhance patient compliance.

The methods of treatment described herein are generally administered toa human female.

A further aspect of the present invention provides formulations of thepresent invention wherein circulating blood level concentrationsfollowing administration of a formulation of the present invention arebioequivalent to circulating blood level concentrations followingadministration of the reference listed drug product, as determinedthrough the completion of a bioequivalence clinical study.

The formulations of the present disclosure may also be vaginallyadministered with or without the co-administration of an orallyadministered estrogen-based pharmaceutical drug product, or patch,cream, gel, spray, transdermal delivery system or otherparenterally-administered estrogen-based pharmaceutical drug product,each of which can include natural, bio-similar, or other synthetic orderived estrogens and/or an administered progestin. As used herein, theterm “progestin” means any natural or man-made substance that hasproperties similar to progesterone.

Modulation of circulating estrogen levels provided via theadministration of a formulation of the present disclosure, if any, arenot intended to be additive to any co-administered estrogen product andits associated circulating blood levels.

The timing of administration of a formulation of the present disclosuremay be conducted by any safe means as prescribed by an attendingphysician. Typically, a patient will insert one capsule intra-vaginallyeach day for 14 days, then one capsule twice weekly for the remainingtime prescribed by such physician. Intra-vaginal insertion may be viathe use of an applicator or without an applicator via use of thepatient's digits. Use of an applicator or otherwise requires due care asto not puncture or tear surrounding tissue.

Estradiol dosage strengths can vary. For formulations of the presentdisclosure, estradiol (or estradiol equivalent to the extent suchestradiol is in a hydrated or other form requiring compensationtherefore) dosage strength of is at least about 1 microgram (mcg), atleast about 2.5 mcg; at least about 5 mcg; at least about 10 mcg, fromabout 1 mcg to about 10 mcg, from about 10 mcg to about 25 mcg, about 1mcg, about 2.5 mcg, about 5 mcg, about 10 mcg and about 25 mcg. Toprotect against adverse effects of estradiol, the lowest possible doseshould be used for treatment of WA and other states set forth herein.

Also provided are soft capsules designed for ease of insertion and tohold the capsule in place until the contents therein are completelyreleased. In various embodiments, softgel capsules in accordance withvarious embodiments are sized to comfortably fit within a human vagina.Thus, the softgel capsules may comprise any dimension capable of fittinginto a human vagina. With reference to FIG. 2, softgel capsule 200 isillustrated. Softgel capsule 200 comprises fill material 202 and gelatin204. Gelatin 204 has a thickness represented by space 208. Space 208comprises a distance of 0.108 inches. The distance from one end ofsoftgel capsule 200 to another is represented by space 206. Space 206comprises a distance of 0.690 inches. The size of softgel capsule 200may also be described by the arc swept by a radius of a given length.For example, arc 210, which is defined by the exterior of gelatin 204,is an arc swept by a radius of 0.189 inches. Arc 212, which is definedby the interior of gelatin 204, is an arc swept by a radius of 0.0938inches. Arc 214, which is defined by the exterior of gelatin 204opposite arc 210, is an arc swept by a radius of 0.108 inches.

Estradiol can be formulated pursuant to the teachings below. Theseformulations can be prepared for vaginal insertion in a single unitdosage form or as otherwise specified herein.

In various embodiments, estradiol is solubilized at least once duringmanufacturing and, in various embodiments, estradiol is solubilized atone point following administration. Solubility may be expressed as amass fraction (% w/w). As used herein, the term “soluble” or“solubilized” means that the estradiol is: at least about 85% soluble,at least 90% soluble, at least 95% soluble and, frequently, is 100%soluble.

In various embodiments, a given mass of estradiol is soluble in a givenmass of vehicle system (e.g., a system that comprises one or moresolubilizing agents), as further described herein. For example, from 10mcg to 25 mcg of estradiol may be soluble in 100 g to 700 g of a vehiclesystem. In various embodiments, once estradiol enters the body, forexample, by being inserted into the vagina, estradiol may continue to besolubilized in the vehicle system or, in further embodiments, estradiolmay form an oil in water emulsion which may be referred to as aself-emulsifying system. As described herein, vehicle systems with lowerHLB values will tend to have estradiol stay solubilized in the vehiclesystem after introduction into the body. As described herein, vehiclesystems with higher HLB value will tend to have estradiol form aself-emulsifying system after introduction into the body.

Upon release of the fill into the vaginal canal following insertion of acapsule of the present disclosure, estradiol may be locally absorbedinto body tissues.

In various embodiments, the solubilizing agent is selected from at leastone of a solvent or co-solvent. Suitable solvents and co-solventsinclude any mono-, di- or triglyceride and glycols, and combinationsthereof.

Solubilized estradiol of the present disclosure is prepared via blendingestradiol with a pharmaceutically acceptable solubilizing agentincluding for example and without limitation, at least one medium chainfatty acid such as medium chain fatty acids consisting of at least onemono-, di-, or triglyceride, or derivatives thereof, or combinationsthereof (collectively, “glycerides”),In various embodiments, solubilizedestradiol of the present disclosure may also comprise at least oneglycol or derivatives thereof or combinations thereof (collectively,“glycols”) and/or combinations of such at least one glyceride andglycol. Glycols may be used as solubilizing agents and/or to adjustviscosity and, thus, may be considered thickening agents, as discussedfurther herein. Optionally added are other excipients including, forexample and without limitation, anti-oxidants, lubricants and the like.Sufficient solubilizing agent(s) is/are used to solubilize estradiol.

Pharmaceutically acceptable solubilizing agents include, for example andwithout limitation, the use of at least one of a caproic fatty acid; acaprylic fatty acid; a capric fatty acid; a tauric acid; a myristicacid; a linoleic acid; a succinic acid; a glycerin; mono-, di-, ortriglycerides and combinations and derivatives thereof; a polyethyleneglycol; a polyethylene glycol glyceride (Gelucire®; GATTEFOSSE SAS,Saint-Priest, France); which can be used herein as a solubilizing agentor as an anionic surfactant); a propylene glycol; a caprylic/caprictriglyceride (Miglyol®; SASOL Germany GMBH, Hamburg); Miglyol includesMiglyol 810, 812, 816 and 829); a caproic/caprylic/capric/laurictriglyceride; a caprylic/capric/linoleic triglyceride; acaprylic/capric/succinic triglyceride; a propylene glycol monocaprylate;propylene glycol monocaprate; (Capmul® PG-8 and 10; the Capmul brandsare owned by ABITEC, Columbus Ohio); a propylene glycol mono- anddicaprylate; a propylene glycol mono- and dicaprate; medium chain mono-and di-glycerides (Capmul MCM); a diethylene glycol mono ester(including 2-(2-Ethoxyethoxy)ethanol: Transcutol®); a diethylene glycolmonoethyl; glyceryl mono- and di-caprylates; propylene glycol;1,2,3-propanetriol (glycerol, glycerin, glycerine) esters of saturatedcoconut and palm kernel oil and derivatives thereof; triglycerides offractionated vegetable fatty acids, and combinations and derivativesthereof. In various embodiments, propylene glycol is used in a cream orointment.

These solubilizers, as defined herein, and combinations thereof, can beused to form solubilized estradiol formulations of the presentdisclosure.

At least one anionic and/or non-ionic surfactant can be used inadditional embodiments of the presently disclosed formulationscontaining solubilized estradiol.

Exemplary non-ionic surfactants may include, for example and withoutlimitation, one or more of oleic acid, linoleic acid, palmitic acid, andstearic acid. In further embodiments, the non-ionic surfactant maycomprise polyethylene sorbitol esters, including polysorbate 80, whichis commercially available under the trademark TWEEN 80® (Sigma Aldrich,St. Louis, Mo.). Polysorbate 80 comprises approximately 60%-70% oleicacid with the remainder comprising primarily linoleic acids, palmiticacids, and stearic acids. Polysorbate 80 may be used in amounts rangingfrom about 5 to 50%, and in certain embodiments, about 30% of theformulation total mass.

In various other embodiments, the non-ionic surfactant is selected fromone or more of glycerol and polyethylene glycol esters of long chainfatty acids, for example, lauroyl macrogol-32 glycerides and/or lauroylpolyoxyl-32 glycerides, commercially available as Gelucire, including,for example, Gelucire 39/01, 43/01 and 50/13. These surfactants may beused at concentrations greater than about 0.01%, and typically invarious amounts of about 0.01%-10.0%, 10.1%-20%, and 20.1%-30%.

Ratios of solubilizing agent(s) to surfactant(s) can vary depending uponthe respective solubilizing agent(s) and the respective surfactant(s)and the desired physical characteristics of the resultant formulation ofsolubilized estradiol. For example and without limitation, Capmul MOMand a non-ionic surfactant can be used at ratios including 65:35, 70:30,75:25, 80:20, 85:15 and 90:10. Other non-limiting examples include:Capmul MOM and Gelucire 39/01 can be used in ratios including, forexample and without limitation, 6:4, 7:3, and 8:2; Capmul MOM andGelucire 43/01 can be used in ratios including, for example and withoutlimitation, 7:3, and 8:2; Capmul MOM and Gelucire 50/13 can be used inratios including, for example and without limitation, 7:3, and 8:2, and9:1.

Another exemplary non-ionic surfactant includes PEG-6 palmitostearateand ethylene glycol palmitostearate, which is available commercially asTEFOSE® 63 (“Tefose 63”; GATTEFOSSE SAS, Saint-Priest, France) which canbe used with, for example, Capmul MOM having ratios of MOM to Tefose 63of, for example, 8:2 and 9:1. Additional examples of solubilizing agentswith non-ionic surfactants include, for example, Miglyol 812:Gelucire50/13 and Miglyol 812:Tefose 63.

Anionic surfactants are well known and can include, for example andwithout limitation: ammonium lauryl sulfate, dioctyl sodiumsulfosuccinate, perfluoro-octane sulfonic acid, potassium lauryl sulfateand sodium stearate.

Non-ionic and/or anionic surfactants can be used alone or with at leastone solubilizing agent or can be used in combination with othersurfactants. Accordingly, such surfactants, or any other excipient asset forth herein, should be used to provide solubilized estradiol, uponrelease from a vaginally-inserted capsule, with consistency of thesolubilized estradiol that promotes absorption and minimizes vaginaldischarge, particularly when compared to the vaginal dischargefrequently occurring following use of a Vagifem tablet.

Moreover, the estradiol in the formulations disclosed herein need not befully solubilized at the time of administration/insertion but, rather,needs to be substantially solubilized at the time of release from thevaginally-inserted capsule. As such, the solubilizing agents taughtherein, with or without additional excipients other than thesolubilizing agents, may be in the liquid or semi-solid form uponadministration providing the estradiol containing solubilizing agentsand other excipients permit flow to fill capsules. To the extent theestradiol is not fully solubilized at the time ofadministration/insertion, the estradiol should be substantiallysolubilized at a temperature of about 37° C. (e.g., body temperature)and, generally, at a pH of about 4.5.

In another embodiment, at least one thickening agent may be added toformulations of the present disclosure. The viscosity of the solubilizedestradiol may depend upon the solubilizing agent(s) used, the additionof other excipients to the formulation preparation and the desired orrequired final viscosity required to optimize absorption of thesolubilized estradiol. In certain embodiments, the surfactant(s)referenced herein above may provide thickening of the solubilizedestradiol such that, upon release, will aid the estradiol in beingabsorbed by the vaginal mucosa while minimizing vaginal discharge,particularly when compared to the vaginal discharge frequently occurringfollowing use of a Vagifem tablet. Examples of other such thickeningagents include, for example and without limitation, hard fats; propyleneglycol; a mixture of hard fat EP/NF/JPE, glyceryl ricinoleate,ethoxylated fatty alcohols (ceteth-20, steareth-20) EP/NF (commerciallyavailable as OVUCIRE® 3460(Gattefosse, Saint-Priest France); a mixtureof hard fat EP/NF/JPE, glycerol monooleate (type 40) EP/NF (commerciallyavailable as OVUCIRE WL 3264; a mixture of hard fat EP/NF/JPE, glycerylemonooleate (type 40) EP/NF(commercially available as OVUCIRE WL 2944);and a mixture of various hard fats (commercially available as WITESPOL®;Sasol Germany GmbH, Hamburg). In various embodiments, the viscosity offormulations in accordance with various embodiments may comprise fromabout 50 cps to about 1000 cps at 25° C.

In other embodiments, one or more muco-adherent agents may be used toassist with mucosal absorption of the solubilized estradiol. Forexample, polycarbophil may be used as an acceptable muco-adherent agent.Other agents include, for example and without limitation, poly (ethyleneoxide) polymers having a molecular weight of from about 100,000 to about900,000, chitosans carbopols including polymers of acrylic acidcross-linked with allyl sucrose or allyl pentaerythritol, polymers ofacrylic acid and C10-C30 alkyl acrylate crosslinked with allylpentaerythritol, carbomer homopolymer or copolymer that contains a blockcopolymer of polyethylene glycol and a long chain alkyl acid ester andthe like. Various hydrophilic polymers and hydrogels may be used. Invarious embodiments, the hydrophilic polymer will swell in response tocontact with vaginal or other bodily secretions, enhancing moisturizingand muco-adherent effects. The selection and amount of hydrophilicpolymer may be based on the selection and amount of pharmaceuticallyacceptable solubilizing agent chosen. The formulation includes ahydrophilic polymer but optionally excludes a gelling agent. Inembodiments having a hydrogel, from about 5% to about 10% of the totalmass may comprise the hydrophilic polymer. In further embodiments,hydrogels may be employed. A hydrogel may comprise chitosan, which swellin response to contact with water. In various embodiments, a creamformulation may comprise PEG-90M.

In additional embodiments, formulations of the present disclosure mayinclude one or more thermoreversible gels, typically of the hydrophilicnature including for example and without limitation, hydrophilic sucroseand other saccharide-based monomers (U.S. Pat. No. 6,018,033, which isherein incorporated by reference).

In other embodiments, a lubricant may be used. Any suitable lubricantmay be used, such as for example lecithin. Lecithin may comprise amixture of phospholipids.

In additional embodiments, an antioxidant is used. Any suitableanti-oxidant may be used such as, for example and without limitation,butylated hydroxytoluene.

In various embodiments, a pharmaceutical formulation comprises about 20%to about 80% solubilizing agent by weight, about 0.1% to about 5%lubricant by weight, and about 0.01% to about 0.1% antioxidant byweight.

The choice of excipient will, to a large extent, depend on factors suchas for example and without limitation, the effect of the excipient onsolubility and stability. Additional excipients used in variousembodiments may include colorants and preservatives. Colorants, forexample, may comprise about 0.1% to about 2% by weight. Preservativesmay, for example and without limitation, comprise methyl and propylparaben, for example, in a ratio of about 10:1, and at a proportion ofabout 0.005% and 0.05% by weight.

As is with all solubilizing agents, excipients and any other additivesused in the formulations described herein, each is to be non-toxic,pharmaceutically acceptable and compatible with all other ingredientsused.

Further provided herein are methods for the treatment of WA and/orestrogen-deficient urinary states comprising administering to a female,typically a human, in need of treatment a non-toxic and pharmaceuticallyeffective dose of a formulation as further provided herein

As referenced above, the formulations of the present disclosure aregenerally vaginally administered via capsules such as soft capsules,including soft gelatin capsules. It is desirable to prepare these softcapsules such that they disintegrate to the extent that substantiallyall of the solubilized estradiol is released upon disintegration,providing rapid absorption of the solubilized estradiol and minimalcapsule residue.

Additional objects of the present disclosure include: providingincreased patient ease of use while potentially minimizing certain sideeffects from inappropriate insertion, minimizing incidence ofvulvovaginal mycotic infection compared to incidence of vulvovaginalmycotic infection due to usage of Vagifem and other currently availableproducts and; decreased resultant genital pruritus compared to thegenital pruritus and/or back pain that may be generated via the use ofVagifem and other currently available products.

EXAMPLES

In various embodiments, a vehicle system is created by dissolving anactive pharmaceutical ingredient (e.g., estradiol) in one or morepharmaceutically acceptable solubilizing agents. A vehicle system maythen be combined with a gel mass to create a final formulation suitablefor use in, for example, a vaginal suppository. In that regard, invarious embodiments, one or more vehicle systems may be combined withone or more gel masses. Other excipients may also be included in thevehicle system in various embodiments.

Example 1

Formulation: Vehicle System

In various embodiments, estradiol active pharmaceutical ingredient isprocured and combined with one or more pharmaceutically acceptablesolubilizing agents. Estradiol may be in micronized form ornon-micronized form. In various embodiments, the final formulationcomprises estradiol in a dosage strength of from about 1 mcg to about 25mcg.

Estradiol is combined with various pharmaceutically acceptablesolubilizing agents in various embodiments. As described above, CapmulMOM, Miglyol 812, Gelucire 39/01, Gelucire 43/01, Gelucire 50/13, andTefose 63(\may, alone or in various combinations, be used as apharmaceutically acceptable solubilizing agent in connection withestradiol.

Solubility of estradiol may affect final formulation stability anduniformity, so care should be taken when selecting an appropriatevehicle system. It is noted that surfactants are typically amphiphilicmolecules that contain both hydrophilic and lipophilic groups. Ahydrophilic-lipophilic balance (“HLB”) number is used as a measure ofthe ratio of these groups. It is a value between 0 and 20 which definesthe affinity of a surfactant for water or oil. HLB numbers arecalculated for nonionic surfactants, and these surfactants have numbersranging from 0-20. HLB numbers >10 have an affinity for water(hydrophilic) and number <10 have an affinity of oil (lipophilic).

In that regard, Gelucire 39/01 and Gelucire 43/01 each have an HLB valueof 1. Gelucire 50/13 has an HLB value of 13. Tefose 63 has an HLB valueof between 9 and 10.

Various combinations of pharmaceutically acceptable solubilizing agentswere combined with estradiol and examined. TABLE 1 contains the results.TABLE 1 contains the following abbreviations: Capmul MOM (“MOM”),Gelucire 39/01 (“39/01”), Gelucire 43/01(“43/01”), Gelucire50/13(“50/13”), and Tefose (“Tefose 63”).

TABLE 1 Physical Physical state @ state @ Melting Dispersion VehicleRoom 37° C. after Viscosity Time @ in water # system Ratio Temperature~30 minutes cps 37° C. 37° C. 1 MCM: 39/01 8:2 Solid Clear liquid 50 @Start: 6 min Small oil 37° C. Finish: 12 min drops on top 2 MCM: 39/017:3 Solid Clear liquid Start: 9 min Finish: 19 min 3 MCM: 39/01 6:4Solid Clear liquid Start: 20 min Finish: 32 min 4 MCM: 43/01 8:2 SolidLiquid with solid particles 5 MCM: 43/01 7:3 Solid Liquid with solidparticles 6 MCM: 50/13 9:1 Liquid/ Liquid/cloudy 140@ Clear afterUniformly cloudy 25° C. 20 min cloudy dispersion 7 MCM: 50/13 8:2Liquid/ Liquid/cloudy 190@ Uniformly cloudy 25° C. cloudy dispersion 8MCM: 50/13 7:3 Semisolid Semisolid 9 MCM: Tefose 9:1 SemisolidLiquid/cloudy 150@ Start: 1 min Uniformly 63 25° C. Finish: 5 min cloudydispersion 10 MCM: Tefose 8:2 Semisolid Semisolid 240@ Uniformly 63 25°C. cloudy dispersion 11 MCM: Tefose 7:3 Semisolid Semisolid 380@Semisolid Uniformly 63 25° C. after 30 min cloudy at dispersion 37° C.,doesn't melt at 41° C. 12 Miglyol 812: 9:1 Semisolid Semisolid 140@ 2phases, 50/13 25° C. oil on top 13 Miglyol 812: 9:1 Liquid/Liquid/cloudy 90@ Start: 1 min 2 phases, Tefose 63 cloudy 25° C. Finish:5 min oil on top

Vehicle systems in TABLE 1 that were liquid or semisolid at roomtemperature were tested using a Brookfield viscometer (BrookfieldEngineering Laboratories, Middleboro, MA) at room temperature. Vehiclesystems appearing in TABLE 1 that were solid at ambient temperature weretested using a Brookfield viscometer at 37° C.

Vehicle systems appearing in TABLE 1 that were solid were placed at 37°C. to assess their melting characteristics. The results are in TABLE 1.It is noted that vehicle system 11 in TABLE 1 did not melt at 37° C. or41° C.

A dispersion assessment of the vehicle systems appearing in TABLE 1 wasperformed. The dispersion assessment was performed by transferring 300mg of each vehicle system in 100 ml of 37° C. water, without agitation,and observing for mixing characteristics.

Example 2

Formulation: Gel Mass

In various embodiments, a vehicle system may be combined with a gelmass. A gel mass may comprise, for example, gelatin (e.g., Gelatin, NF(150 Bloom, Type B)), hydrolyzed collagen (e.g., GELITA®, GELITA AG,Eberbach, Germany), glyercin, sorbitol special, and/or other suitablematerials in varying proportions. Sorbitol special may be obtainedcommercially and may tend to act as a plasticizer and humectant.

Gel masses A through F were prepared according to the formulations in

TABLE 2. Gel masses A through F differ in the proportion of one or morecomponents, for example.

TABLE 2 Gel A Gel B Gel C Gel D Gel E Gel F Ingredient % w/w % w/w % w/w% w/w % w/w % w/w Gelatin, NF (150 Bloom, Type B) 41.0 41.0 41.0 41.043.0 43.0 Glycerin 99.7%, USP 6.0 6.0 6.0 6.0 18.0 18.0 SorbitolSpecial, USP 15.0 15.0 15.0 15.0 GELITA (hydrolyzed collagen) 3 3.0Citric acid 0.1 0.5 1 0.1 Purified Water 35.0 37.9 37.5 37.0 36.0 38.9Total 100.0 100.0 100.0 100.0 100.0 100.0 Dissolution gel strips, Avg of3 48 min 50 min 75 min 70 min (500 ml DH2O, 50 rpm @ 37° C.) (42, 45,58) (50, 51, 50) (76, 75, 74) (70, 71, 70) Dissolution gel strips, Avgof 3 72 min 82 min (500 ml pH 4 buffer, 50 rpm @ 37° C.) 70 min 84 min

Each gel mass A through F was prepared at a temperature range from about45° C. to about 85° C. Each molten gelatin mass A through F was castinto a film, dried and cut into strips. The strips were cut into uniformpieces weighing about 0.5 g, with about 0.5 mm thickness. Strips wereplaced into a USP Type 2 dissolution vessel in either water or pH 4buffer solution and the time for them to completely dissolve wasrecorded and listed in TABLE 2. It is noted that gel mass A has thefastest dissolution in both water and pH 4 buffer solution.

Example 3

Formulation: Final Formulation

Various combinations of vehicle systems from TABLE 1 and gel masses fromTABLE 2 were prepared. The combinations are shown in TABLE 3.

TABLE 3 Trial Vehicle system Ratio Batch Size g Gel 1 MCM:39/01 8:2 750A 2 MCM:50/13 8:2 750 A 3 MCM:Tefose 63 8:2 750 A 4 MCM:Tefose 63 8:2750 B 5 Miglyol 812:Tefose 63 9:1 750 A

Estradiol was combined with each vehicle system so that about 10 mcg ofestradiol was contained within 300 mg of each vehicle system. Batch sizewas as listed in TABLE 3. Each 300 mg of vehicle system was combinedwith about 200 mg of the listed gel mass. Thus, for example, in Trial 1,MCM:39/01 in an 8:2 ratio was combined with gel A and 10 mcg ofestradiol. In each final dosage, Trial 1 comprised 300 mg of vehiclesystem, 200 mg of gel mass and 10 mcg of estradiol. It should be noted,however, that in various embodiments the total mass of vehicle system,gel mass, and estradiol may be from about 100 mg to about 1000 mg.

Each combination of vehicle system, estradiol, and gel mass may besuitable for use in, for example, a vaginal suppository.

Example 4

Cream

A vehicle system for use in an ointment or cream may be prepared inaccordance with TABLE 4, below. TABLE 4 is a subset of TABLE 1, above.The vehicle systems of TABLE 4 have viscosity and physical states thatare particularly suited for use in an ointment or cream.

TABLE 4 Physical Physical state Melting state @ @ 37° C. after ViscosityTime @ Dispersion in # Vehicle system Ratio RT ~30 minutes cps 37° C.water 37° C. 8 MCM: 50/13 7:3 Semisolid Semisolid 9 MCM: Tefose 63 9:1Semisolid Liquid/cloudy 150@ Start: 1 min Uniformly 25° C. Finish: 5 mincloudy dispersion 10 MCM: Tefose 63 8:2 Semisolid Semisolid 240@Uniformly 25° C. cloudy dispersion 11 MCM: Tefose 63 7:3 SemisolidSemisolid 380@ Semisolid Uniformly 25° C. after 30 min cloudy at 37° C.,dispersion doesn't melt at 41° C. either 12 Miglyol 812: 9:1 SemisolidSemisolid 140@ 2 phases, oil 50/13 25° C. on top

Example 5

Process

With reference to FIG. 1, a method of making a fill material 100 isshown. Step 102 comprises heating a solubilizing agent to 40° C.±5° C.Heating may be accomplished through any suitable means. The heating maybe performed in any suitable vessel, such as a stainless steel vessel.The solubilizing agent may be any such solubilizing agent describedherein, for example, Capmul MOM.

Step 104 comprises mixing Gelucire with the solubilizing agent. As usedherein, any form of Gelucire may be used in step 104. For example, oneor more of Gelucire 39/01, Gelucire 43/01, Gelucire 50/13. may be usedin step 104. Mixing may be facilitated by an impeller, agitator, orother suitable means. Step 104 may be performed under an inert orrelatively inert gas atmosphere, such as nitrogen gas. Mixing may beperformed in any suitable vessel, such as a stainless steel vessel.

Step 106 comprises mixing estradiol into the mixture of the solubilizingagent and Gelucire. The estradiol may be mixed in micronized ornon-micronized form. Mixing may occur in a steel tank or otheracceptable container. Mixing may be facilitated by an impeller,agitator, or other suitable means. Step 106 may be performed under aninert or relatively inert gas atmosphere, such as nitrogen gas. Invarious embodiments, however, the addition of estradiol may be performedprior to step 104. In that regard, in various embodiments, step 106 isperformed prior to step 104.

Step 110 comprises preparing the gel mass. Any of the gel massesdescribed herein may be used in step 110. In that regard, gelatin (e.g.,Gelatin, NF (150 Bloom, Type B)), hydrolyzed collagen, glycerin, and/orother suitable materials may be combined at a temperature range fromabout 45° C. to about 85° C. and prepared as a film. Mixing may occur ina steel tank or other acceptable container. Mixing may be facilitated byan impellor, agitater, or other suitable means. Step 110 may beperformed under an inert or relatively inert gas atmosphere, such asnitrogen gas. Step 112 comprises degasing. The resulting mixture fromstep 112 may comprise a fill material suitable for production into asoftgel capsule.

In step 112, a soft gel capsule is prepared by combining the materialobtained in step 106 with the gel mass of step 110. The gel film may bewrapped around the material, partially or fully encapsulating it. Thegel film may also be injected or otherwise filled with the materialobtained in step 106.

Step 112 may be performed in a suitable die to provide a desired shape.Vaginal soft gel capsules may be prepared in a variety of geometries.For example, vaginal soft gel capsules may be shaped as a tear drop, acone with frustoconical end, a cylinder, a cylinder with larger “cap”portion, or other shapes suitable for insertion into the vagina. Vaginalsoft gel capsules in accordance with various embodiments may or may notbe used in connection with an applicator.

1.-50. (canceled)
 51. A vaginal suppository comprising: a) atherapeutically effective amount of estradiol; and b) a solubilizingagent, wherein the solubilizing agent comprises at least one C6-C12fatty acid or a glycol, monoglyceride, diglyceride, or triglycerideester thereof.
 52. The vaginal suppository of claim 51, wherein theestradiol is solubilized.
 53. The vaginal suppository of claim 51,wherein the estradiol is micronized.
 54. The vaginal suppository ofclaim 51, wherein the estradiol is hydrated.
 55. The vaginal suppositoryof claim 51, wherein the suppository comprises from about 1 microgram toabout 25 micrograms of estradiol.
 56. The vaginal suppository of claim55, wherein the suppository comprises from about 1 microgram to about 10micrograms of estradiol.
 57. The vaginal suppository of claim 55,wherein the suppository comprises about 10 micrograms of estradiol. 58.The vaginal suppository of claim 55, wherein the suppository comprisesabout 5 micrograms of estradiol.
 59. The vaginal suppository of claim55, wherein the suppository comprises about 2.5 micrograms of estradiol.60. The vaginal suppository of claim 51, wherein the suppository furthercomprises a capsule.
 61. The vaginal suppository of claim 60, whereinthe capsule is a soft gelatin capsule.
 62. The vaginal suppository ofclaim 51, wherein the solubilizing agent comprises at least one of anester of caproic fatty acid, an ester of caprylic fatty acid, an esterof capric fatty acid, and combinations thereof
 63. The vaginalsuppository of claim 51, wherein the solubilizing agent comprises amonoglyceride, diglyceride, or triglyceride ester of the at least oneC6-C12 fatty acid.
 64. The vaginal suppository of claim 63, wherein thesolubilizing agent comprises a caprylic / capric triglyceride.
 65. Avaginal suppository comprising: a) a therapeutically effective amount ofestradiol; b) a caprylic / capric triglyceride; c) a non-ionicsurfactant comprising PEG-6 palmitostearate and ethylene glycolpalmitostearate; and d) a soft gelatin capsule.
 66. A method of treatingan estrogen-deficient state, the method comprising administering to afemale in need thereof, a vaginal suppository comprising: a) atherapeutically effective amount of solubilized estradiol; and b) asolubilizing agent, wherein the solubilizing agent comprises at leastone C6-C12 fatty acid or a glycol, monoglyceride, diglyceride, ortriglyceride ester thereof.
 67. The method of claim 66, wherein theestrogen-deficient state is vulvovaginal atrophy.
 68. The method ofclaim 66, wherein the estrogen-deficient state is an estrogen-deficienturinary state.
 69. The method of claim 66, wherein theestrogen-deficient state is selected from the group consisting of:vulvovaginal atrophy, dysuria, dyspareunia, estrogen-deficient urinarystates, and vaginal bleeding associated with sexual activity.